This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.

Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Secondary Outcome Measures:

Progression-free Survival in All Participants [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Overall Survival in All Participants [ Time Frame: Day 1 until death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases [ Time Frame: Day 1 until death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

Number of Participants With OR as Assessed by the Investigator and Independent Review [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

Number of Participants With OR Following Cross-over to Trametinib [ Time Frame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 2.72 months) ] [ Designated as safety issue: No ]

OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1.

Duration of Response (DR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classifed as Confirmed Responders (CR or PR) as Assessed by the Investigator and Independent Review [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

DR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DR for the investigator-assessed (INVA) and independently-assessed (INDA) response data were summarized per RECIST, Version 1.1.

DR for All Confirmed Responders (CR or PR) as Assessed by the Investigator or Independent Review [ Time Frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 4.8 months) ] [ Designated as safety issue: No ]

DR is defined as thetime from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DR for the INVA and INDA response data was summarized per RECIST, Version 1.1.

DR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator [ Time Frame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 2.72 months) ] [ Designated as safety issue: No ]

DR is defined as the time from the first documented evidence of CR (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DR data were summarized per RECIST, Version 1.1.

PFS Following Cross-over to Trametinib as Assessed by the Investigator [ Time Frame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 2.72 months) ] [ Designated as safety issue: No ]

PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory

Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. Prior treatment with immunotherapy (with the exception of prior ipilimumab, which is only allowed if given in the adjuvant setting), cytokine therapy, biological or vaccine regimen is permitted. Prior use of sorafenib is allowed

Women of childbearing potential and men with reproductive potential must agree to use effective contraception during the study. Additionally women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1

Adequate screening organ function

Exclusion Criteria:

Any prior use of BRAF inhibitors or MEK inhibitors.

Subjects who have received dacarbazine or paclitaxel prior to randomization will not be eligible to receive the same chemotherapy as study medication (i.e. a subject who received prior dacarbazine cannot receive dacarbazine on this trial and would thus receive paclitaxel if randomized to the control arm)

History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above

Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)

Brain metastases with the following exceptions that are ALL confirmed by the GSK Medical Monitor:

All known lesions must be previously treated with surgery or stereotactic radiosurgery, and Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to randomization (must be documented with two consecutive MRI or CT scans using contrast), and asymptomatic with no corticosteroids requirement for ≥ 30 days prior to randomization, and no enzyme-inducing anticonvulsants for ≥ 30 days prior to randomization

History or evidence of cardiovascular risk including any of the following:

QTcB ≥ 480 msec.

History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible

History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association

History of interstitial lung disease or pneumonitis

History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):

History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).

Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as:

Evidence of new optic disc cupping.

Intraocular pressure > 21 mm Hg as measured by tonography

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01245062